Antiretroviral therapy is effective in preventing HIV replication, however it does not eliminate all HIV proviruses, resulting in the presence of long-lasting reservoirs that re-kindle infection following cessation of treatment. Thus HIV infected individuals are required to remain on therapy for life, to prevent viral rebound. If we can control or prevent viral rebound, we may be able to provide patients a drug-free remission period, or a functional cure to HIV disease. Project 2 is designed to determine whether enhanced or genetically engineered immune cells can help to delay or minimize viral rebound. We will utilize cutting edge humanized mouse models, a novel barcoded virus reporter system, and several anti-HIV chimeric antigen receptors (CARs) to accomplish 3 aims: 1) Evaluate the effects of engineered anti-HIV T cells on HIV rebound following cessation of ART; 2) Evaluate the effects of natural killer cells on HIV rebound following cessation of ART; 3) Determine if reduction of the latent reservoir influences viral rebound after cessation of ART. Together these aims should allow us to better understand factors controlling viral rebound and determine whether genetic enhancement of cellular immunity or manipulation of innate immune responses can affect viral rebound. If so, this may point the way towards a new adjunctive therapeutic approach for HIV disease.